title: High SIRT1 expression is a negative prognosticator in pancreatic ductal adenocarcinoma.
abstract: BACKGROUND
  Several lines of evidence indicate that Sirt1, a class III histone deacetylase (HDAC) is implicated in the initiation and progression of malignancies and thus gained attraction as druggable target. Since data on the role of Sirt1 in pancreatic ductal adenocarcinoma (PDAC) are sparse, we investigated the expression profile and prognostic significance of Sirt1 in vivo as well as cellular effects of Sirt1 inhibition in vitro.
  
  
  METHODS
  Sirt1 expression was analyzed by immunohistochemistry in a large cohort of PDACs and correlated with clinicopathological and survival data. Furthermore, we investigated the impact of overexpression and small molecule inhibition on Sirt1 in pancreatic cancer cell culture models including combinatorial treatment with chemotherapy and EGFR-inhibition. Cellular events were measured quantitatively in real time and corroborated by conventional readouts including FACS analysis and MTT assays.
  
  
  RESULTS
  We detected nuclear Sirt1 expression in 36 (27.9%) of 129 PDACs. SIRT1 expression was significantly higher in poorly differentiated carcinomas. Strong SIRT1 expression was a significant predictor of poor survival both in univariate (p = 0.002) and multivariate (HR 1.65, p = 0.045) analysis. Accordingly, overexpression of Sirt1 led to increased cell viability, while small molecule inhibition led to a growth arrest in pancreatic cancer cells and impaired cell survival. This effect was even more pronounced in combinatorial regimens with gefitinib, but not in combination with gemcitabine.
  
  
  CONCLUSIONS
  Sirt1 is an independent prognosticator in PDACs and plays an important role in pancreatic cancer cell growth, which can be levered out by small molecule inhibition. Our data warrant further studies on SIRT1 as a novel chemotherapeutic target in PDAC.
authors.affiliation: Institute of Pathology, and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. albrecht.stenzinger@med.uni-heidelberg.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.forename: Frederick
authors.initials: F
authors.lastname: Klauschen
authors.forename: Bruno
authors.initials: B
authors.lastname: Sinn
authors.forename: Katja
authors.initials: K
authors.lastname: Lorenz
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goeppert
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Alexander
authors.initials: A
authors.lastname: Muckenhuber
authors.forename: Carsten
authors.initials: C
authors.lastname: Kamphues
authors.forename: Marcus
authors.initials: M
authors.lastname: Bahra
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005500:Follow-Up Studies; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009536:Niacinamide / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D011379:Prognosis; D011744:Pyrimidinones / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D009281:Naphthalenes; D011744:Pyrimidinones; D011799:Quinazolines; C510718:cambinol; D009536:Niacinamide; D056564:Sirtuin 1; D000077156:Gefitinib